Traditional Chinese and western medicine for the prevention of deep venous thrombosis after lower extremity orthopedic surgery: a meta-analysis of randomized controlled trials

Background Chinese herbal medicine has traditionally been considered to promote blood circulation to remove obstruction in the channels and clear pathogenic heat to drain dampness effects. We conducted this meta-analysis to evaluate its benefits for the prevention of deep venous thrombosis (DVT) after lower extremity orthopedic surgery. Methods Relevant, published studies were identified using the following keywords: lower extremity orthopedic surgery, arthroplasty, joint replacement, fracture, traditional Chinese and western medicine, Chinese herbal medicine, deep venous thrombosis (DVT), and Venous thromboembolism (VTE). The following databases were used to identify the literature consisting of RCTs with a date of search of 31 May 2017: PubMed, Cochrane Library, Web of knowledge, the Chinese National Knowledge Infrastructure Database, the Chongqing VIP Database, the Chinese Biomedical Database, and the Wanfang Database (including three English and four Chinese databases). All relevant data were collected from studies meeting the inclusion criteria. The outcome variables were the incidence rate of DVT, activated partial thromboplastin time (APTT), prothrombin time (PT), and d-dimer; subcutaneous hematoma; and other reported outcomes. RevMan5.2. software was adopted for the meta-analysis. Results A total of 20 published studies (1862 cases) met the inclusion criteria. The experimental group, 910 patients (48.87%), received the Chinese herbal medicine or traditional Chinese and western medicine for prevention of DVT; the control group, 952 patients (51.13%), received the standard western treatment. The meta-analysis showed that traditional Chinese and western medicine therapy reduced the incidence rates of DVT significantly when compared with controls (risk ratio [RR] = 0.40; 95% CI, 0.30 to 0.54; P < 0.00001), and the d-dimer was lower in the experimental group (P = 0.01). Besides, the incidence rate of subcutaneous hematoma was lower in the experimental group (P < 0.0001). However, no significant difference was found in the PT (P = 0.98) and APTT (P = 0.75) in two groups. No serious adverse events were reported. Conclusion Traditional Chinese and western medicine therapy may be a safe, effective prevention modality for DVT after lower extremity orthopedic surgery. Further rigorously designed, randomized trials are warranted.


Background
Deep vein thrombosis (DVT) is one of the most common complications after lower extremity orthopedic surgery, several patients may develop into pulmonary embolism (PE), and some serious can lead to death [1,2]. A large number of researches show that patients undergoing lower extremity orthopedic surgery are the high-risk group for venous thromboembolism (VTE). In the absence of any preventive measures, the incidence of DVT after surgery was up to 40-60%, the incidence of PE was 20%, and the fatal PE was 0.1-2% [1]. Thus, guidelines for the prevention of postoperative anticoagulation have been recommended in various countries after excluding the contraindication [1][2][3][4][5][6].
Traditional Chinese medicine theory holds that DVT is the category of "pulse closed" and "femoral swelling," and the main treatment is to promote blood circulation to remove blood stasis. Traditional Chinese herb not only has the effects of analgesic and anti-inflammatory, but also can effectively improve blood circulation [7]. Thus, in conducting the traditional Chinese medicine syndrome differentiation, adjuvant therapy on the basis of western medicine treatment is paying more attention to the theory of traditional Chinese medicine that diagnosis and treatment are based on an overall analysis of the illness and the patient's condition and also insisting on treating both principal and secondary aspect of disease. Therefore, the advantages of the combination of traditional Chinese and western medicine are becoming more and more prominent in the treatment and prevention of thrombotic diseases.
Although there is a long history of traditional Chinese medicine for prevention and treatment of DVT in ancient China, the necessary quantitative evidence to estimate treatment effects is still lacking. Therefore, we conducted this meta-analysis to evaluate the efficacy and safety of RCTs involving traditional Chinese and western medicine for the prevention of DVT after lower extremity orthopedic surgery, expecting to provide evidencebased medical proof for clinical medicine.

Search strategy
A comprehensive search for studies about traditional Chinese and western medicine for the prevention of DVT after lower extremity orthopedic surgery was conducted through the online database. We searched PubMed, Cochrane Library, Web of knowledge, the Chinese National Knowledge Infrastructure Database, the Chongqing VIP Database, the Chinese Biomedical Database, and the Wanfang Database (including three English and four Chinese databases) up to May 31, 2017. The following keywords were used: ("traditional Chinese and western medicine" or "traditional Chinese medicine" or "Chinese herbal medicine" or "Chinese herb") in combination with (("lower extremity orthopedic surgery" or "arthroplasty" or "joint replacement" or "fracture") and ("deep venous thrombosis" or "Venous thromboembolism")). Additional studies were identified from references of retrieved articles. The duplicated articles were eliminated using Endnote software (EndNote X7).

Inclusion and exclusion criteria
Trials were eligible if they were randomized controlled trials (RCTs) recruiting participants with lower extremity orthopedic surgery (including total hip replacement [THR], total knee replacement [TKR], or hip fracture surgery [HFS]) and so on). These included patients in the experimental group who received the treatment of traditional Chinese and western medicine for the prevention of DVT after orthopedic surgery, while those in the control group were subjected to standard western therapy for DVT. All studies cited could provide relevant data. There was no language restriction in the literature search.
In order to evaluate the independent effects of the traditional Chinese and western medicine intervention, we excluded (1) conference abstracts, review articles, animal studies, cadaveric studies, in vitro studies, or articles published in a form other than clinical trials; (2) any control group that included traditional Chinese therapies; (3) literatures without relevant postoperative indicators or quantitative data; and (4) repeated published literature.

Selection of studies
Two authors (Zhu and Song) independently screened all potential eligible studies. Titles and abstracts were first screened to exclude irrelevant citations. Full text of all articles of potentially relevant abstracts were retrieved and screened according to the study inclusion and exclusion criteria.

Data extraction
The two investigators (Zhu and Qian) reviewed the titles and abstracts, carefully read the full texts according to preset inclusion criteria, and extracted the data from included studies using a pre-designed data extraction table. Study characteristics that were extracted included the author, publication year, sample size, age and gender of subjects, and detailed information of two groups, outcome measures, summary of results, main conclusion, and adverse reactions. The data were arranged into experimental form and Excel spreadsheets in duplicate. All data extraction work was done by the two authors independently. When any inconsistency arose, the issues were either resolved by a third investigator (Chen) or negotiated by both the original investigators.

Definition of outcome events
The main outcome events were the incidence of DVT, the outcomes of D-dimer, prothrombin time (PT), and thromboplastin time (APTT). The secondary events were any adverse events (including hematoma, hemorrhage, and so on) and other reported outcomes.

Quality assessment
Two reviewers (Zhu and Song) independently conducted the methodological quality of all included studies. The cases were reviewed and screened carefully for data of interest. Any disagreement between the investigators was resolved with mutual consensus in the presence of the third author (Chen). The quality of studies was estimated according to the Newcastle-Ottawa Scale (NOS) [8].

Statistical method
For each included study, the weighted mean differences (WMD) at 95% confidence intervals (CI) were calculated for continuous outcomes, while odds ratio (OR) at 95% confidence intervals (CI) were calculated for dichotomous outcomes. Heterogeneity among the studies was assessed using the chi-squared and I-squared (I 2 ) tests. A fixed effect model was applied when I 2 < 50%, whereas a random effect model was applied when I 2 > 50%. All analyses were completed with Review Manager 5.2 [9,10] software (Cochrane Collaboration, Oxford, UK) and a P value < 0.05 was considered statistically significant. Funnel plots were used to assess potential bias [11].

Basic characteristics of included studies
The characteristics of the 20 RCTs are summarized in Tables 1, 2 There are a total of 910 participants who received traditional Chinese and western medicine (experimental group) and 952 who received standard western treatment (control group). All 20 papers reported the incidence rate of DVT after lower extremity orthopedic surgery, 9 papers had data on D-dimer, 8 papers had the outcomes of PT and APTT, and 4 papers reported subcutaneous hematoma. All papers had similar distributions of sex, age, and types of surgery. The included studies are described in Table 1. Table 2 includes the composition and efficacy of traditional Chinese medicine prescription in the experimental groups. The incidence rate of DVT are listed in Table 3, the data of APTT and PT are in Table 4, and the outcome of D-dimer is described in Table 5. The date of subcutaneous hematoma is summarized in Table 6.

Quality assessment
The quality assessment of the trials was performed using the Newcastle-Ottawa Scale. The detailed results are presented in Fig. 7. The overall quality of trials was moderate. Randomization was adequate in 20 trials (100%). All studies reported the similarity of study groups at baseline (100%). Outcome assessors blinded in 2 trials (10%), unclear in 18 trials (90%), the bias of blinding to patients in 2 trials (10%), unclear in 18 trials (90%). Allocation concealment and intention to treat items were difficult to assess from reported information.

Discussion
DVT is a common complications after lower extremity orthopedic surgery, especially in THA, TKA, and hip fracture. The incidence of VTE is very high in patients who do not receive preventive anticoagulation therapy, some serious can develop into PE. The rescue success of fatal PE is extremely low and without any aura, which is one of the most common causes of non-expected death in the hospital. Therefore, the universality of DVT and the severity of PE after lower extremity orthopedic surgery have been formed into a consensus among doctors in different countries. Furthermore, lots of studies and guidelines have demonstrated that patients received lower extremity orthopedic surgery should begin preventive anticoagulation as soon as possible after ruled out any contraindications. At present, the mechanical preventive measures of DVT includes graduated compression stocking (GCS), intermittent pneumatic compression devices (IPC), venous foot pump (VFP), early mobilization, and so on. However, the commonly used anticoagulant drugs, such as the unfractionated and warfarin from the last century to low molecular weight heparin (LMWH), and burgeonsing direct Xa factor inhibitors. Besides, the latest guidelines of AAOS also explicitly recommended aspirin as a drug for the prevention of DVT after lower extremity orthopedic surgery [2].
For Chinese herbal medicine, also called traditional Chinese medicine, most western scholars may think that it is not a science, but an experience, and it is not supported by any theoretical foundation. However, in fact, using the traditional Chinese herbal medicine for prevention and treatment of thrombosis has been a thousand years of history in China; there is its own unique advantages. Promoting circulation and removing stasis and clearing heat and promoting diuresis are the main theory in the prevention and treatment of DVT [32,33].
A total of 20 researched involving 1862 patients were included in our study; all papers are RCTs. The results of meta-analysis showed that traditional Chinese and western medicine therapy had obvious advantages in the prevention of DVT after lower extremity orthopedic  surgery; the incidence rate of DVT was significantly lower than that of the control group with statistical difference. And the values of D-dimer was lower in the experimental group than those of the control group, with statistical difference. However, there was no statistical difference between PT and APTT in the two groups; it showed that traditional Chinese medicine did not increase the risk of bleeding or hemorrhage. Four RCTs described the incidence of subcutaneous hematoma after surgery; amazingly, meta-analysis indicated a significantly lower number of patients on the experimental group undergoing the subcutaneous hematoma compared to that in the control group, with statistical difference. In addition, there were no reports of any serious complications, demonstrating the safety of the combination of traditional Chinese and western medicine in the prevention of DVT. Despite the lack of knowledge about the biological mechanisms of traditional Chinese medicine in the prevention of DVT, the synergy between the efficacy of Chinese herbal medicine and western medicine may play a major role in symptomatic treatment.
First, ingredients of traditional Chinese medicine can promote pain relief and flow of Qi (vital energy), reduce swelling and remove blood stasis, and bring more nutrients and oxygen to the healing tissues, so that blood circulation is improved and obstruction in the channels is removed [34]. Second, researches have suggested that  Fig. 3 The effect on PT of two groups out-off-balance between the coagulation and anticoagulation system is a major reason to cause human body's hyperglycemia during the process of DVT formation. Third, traditional Chinese medicine theory studies have suggested that the basic pathogenesis of deep venous thrombosis is blood stasis in the meridians.
Some studies have already proved that traditional Chinese medicine has therapeutic efficacy in DVT. For example, Honghua [35] injection has optimal therapeutic effect by its anti-thrombosis, anti-myocardial ischemia, microcirculation improvement, antioxidant, and other aspects. Danggui [36] can expand blood vessels and inhibit platelet aggregation; besides, it also has the effect on anti-oxidation and free radical elimination. These benefits are largely dependent on its ingredients of polysaccharides, phthalates, coumarins, flavonoids, volatile oil compounds, and others. Chuanxiong [37] has optimal therapeutic effect by its bio-activity such as anti-tumor, anti-inflammation, anti-apoptosis, and vasodilation. Danshen [38] can prevent thrombosis by expanding the peripheral vessels and increasing the activity of plasmin. Some researches also indicated Danshen can exert its antithrombotic effect through inhibiting platelet aggregation (by increasing cAMP levels and inhibiting TXA2 synthesis in platelets) and improving the status of hemorheology property of the blood (by decreasing blood viscosity and shortening erythrocyte electrophoresis time).
These researches suggested that traditional Chinese medicine can eliminate obstruction in the channels for the patients with DVT by its effects on swelling alleviation, blood stasis removal, and blood circulation promotion. Cumulatively, these beneficial reports may cause the improvement of the clinical symptoms of deep venous thrombosis after lower extremity orthopedic surgery. This is the first meta-analysis to evaluate the efficacy and safety of traditional Chinese and western medicine for the prevention of DVT after lower extremity orthopedic surgery, and all researches are RCTs to ensure the scientific reliability and rigor. But there are some limitations. First, the overall methodological quality of the RCTs was moderate. Many of the trials selected for Fig. 4 The effect on APTT of two groups Fig. 5 The effect on D-dimer of two groups inclusion contained some methodological deficiencies, so the number of truly high-quality studies eligible under these standards was too small. This might have caused bias. In the final results, some of the studies mentioned the word "random" but did not describe the specific method employed and did not mention whether a blind methodology was used or whether it had any dropout or not, which might cause a certain degree of bias risk. Second, all RCTs are unanimously published in Chinese academic journals due to the particularity of study contents, so we did not use statistical methods to test for publication bias. Third, some studies did not use the recommended guidelines for the prevention of DVT, and there is no explicit mention that if they conducted the evaluation of DVT after 11-to 35-day anticoagulant therapy in accordance with the guidelines. Besides, the definite location of thrombosis and whether there is some bleeding and other side effects were not mentioned. Therefore, we still need more large sample, highquality, and multi-center RCTs to support the efficacy and safety of traditional Chinese and western medicine for the prevention of DVT after lower extremity orthopedic surgery.

Conclusion
Traditional Chinese medicine have the ability of swelling reduction and blood stasis removal, also can promote blood circulation to remove obstruction in the channels for patients. Cumulatively, these beneficial reports may result in reducing the incidence rate of DVT after lower extremity orthopedic surgery. Despite moderate quality of trials included and the existed bias of researches, Chinese traditional medicine therapy with a history dating back thousands of years radiates a glimmer of hope in the prevention of DVT after lower extremity orthopedic surgery. However, more high-quality, rigorously designed, and well-controlled RCTs are needed to support the clinical application of traditional Chinese medicine for the prevention of DVT.